Vascular patency and adequate blood flow are essential components of normal placental function. Conditions that trigger prothrombotic changes in the placenta compromise blood flow and have serious consequences for both the mother and the baby. Consequences include fetal growth restriction, early or late fetal death and maternal hypertensive disorders, such as preeclampsia. These are disorders of multifactorial origin that affect more than 5% of all pregnancies. The human placenta forms an unusual vascular bed not found anywhere else in the body. The maternal vascular spaces in the placenta are lined by fetal trophoblast cells, rather than the maternal vascular endothelium. It is unclear how blood flow is maintained in these vascular spaces and what leads to pathological thrombosis. The dynamics of interplay between coagulation and inflammation remain undefined; these are likely to of significance since the placenta must evade immune surveillance in order to thrive. We have developed a murine model of thrombophilia-precipitated placental failure and fetal loss that occurs in the absence of thrombosis. We find that this model is driven by thrombin-mediated platelet activation and that pregnancy outcome is improved by heparin treatment, but not by treatment with hirudin, fondaparinux or a direct Xa inhibitor. Using this model we test the hypothesis that thrombin-mediated activation of maternal platelets causes placental failure through mechanisms that do not require thrombosis or platelet aggregation. We examine the contributions of platelet receptors IIb3, GPIB-V-IX and GPVI, and platelet release reaction to placental failure, and determine if placental failure is associated with impaired differentiation of trophoblast cells or the recruitment of immune cells. We evaluate the contributions of upstream extrinsic and intrinsic pathway components to disease pathology, based on the rationale that platelet activation can invoke the activation of intrinsic pathway components or recruit TF-mediated inflammation. We test the hypothesis that placental failure in this model is caused by the disruption of protein C activation on trophoblast cell surface. Building on our previous work, we test the hypothesis that the anticoagulation function of heparin is not required for its beneficial effect. We expand our studies to a second model of placental failure in which a deficiency of estrogen sulfotransferase causes placental thrombosis associated with increased sensitivity of maternal platelets to thrombin and is improved by heparin treatment. Proposed studies investigate the molecular details of platelet recruitment to the placenta and the mechanisms by which by which platelets disrupt placental function. They test the validity of current paradigms in coagulation biology in the in vivo context of placental development and function. These are much-needed investigations into platelet and coagulation activities at the feto-maternal interface with direct significance for pregnancy disorders.